Targeting Tumor Cell Stemness: A New Strategy in Colon Cancer Treatment

Colon cancer remains one of the most prevalent and deadly cancers worldwide, ranked third in diagnosis and leading in cancer-related mortality. A key obstacle in effectively managing colon cancer is the presence of cancer stem cells—powerful minority populations within tumors that drive growth, resist conventional treatments, and often cause relapse. These cells possess 'stemness' properties, allowing them to self-renew and differentiate, making them crucial targets for therapy.

Recent research highlights the importance of understanding the molecular mechanisms controlling stemness in colon cancer. Among the critical molecules involved are the homeobox transcription factors CDX1 and CDX2, which maintain intestinal cell identity and have been shown to inhibit tumor growth. Conversely, β-catenin is a well-known protein that promotes oncogenic activity and cancer progression. Although previous studies indicated that CDX1 and CDX2 suppress tumor growth, their exact role in counteracting β-catenin-driven stemness remained unclear.

A groundbreaking study led by Professor Koji Aoki at the University of Fukui, Japan, published in the journal Cell Death & Disease in May 2025, sheds light on this process. The research team investigated how CDX1 and CDX2 influence gene expression related to stemness by using genetically engineered mice, human colon cancer cell lines, and organoid cultures. They found that losing CDX1 or both CDX1 and CDX2 increased tumor aggressiveness, with higher levels of stemness markers like LGR5 and CD44, and greater invasiveness.

Reintroducing CDX1 or CDX2 into cancer cells significantly reduced the expression of these stemness-associated genes, indicating their suppressive role. At the molecular level, CDX1/2 were observed to bind near the LGR5 gene, competing with β-catenin, and importantly, they decreased the presence of essential transcriptional components like RNA polymerase II, DSIF, and PAF1 around the gene’s starting point.

The analysis revealed that CDX1/2 interfere directly with β-catenin’s ability to assemble active transcription complexes, critical for gene expression related to stemness. By preventing β-catenin from interacting with these complexes through their homeodomains, CDX1/2 act as gatekeepers, shutting down pathways that promote cancer stemness.

The study emphasizes that the DSIF and PAF1 complexes serve as central platforms integrating signals that regulate tumor behavior. Targeting these complexes and understanding how they influence gene expression could open new avenues for therapies aimed at eradicating cancer stem cells and preventing relapse.

This discovery underscores the potential of developing drugs that modulate the activity of transcriptional complexes involved in stemness, paving the way for more effective colon cancer treatments. Further research into these molecular pathways might deliver innovative strategies to suppress tumor progression and improve patient outcomes.

For more information, see the full study: Koji Aoki et al, "CDX1 and CDX2 suppress colon cancer stemness by inhibiting β-catenin-facilitated formation of Pol II–DSIF–PAF1C complex," Cell Death & Disease, 2025. Source: https://medicalxpress.com/news/2025-07-suppressing-tumor-cell-stemness-colon.html.